Our long term goal is to improve the clinical success of revised joint replacements by improving their fixation. We developed our experimental model of revision joint replacement in an earlier funding period, and established its correspondence with clinical studies. We have shown that interventions yielding superior fixation of primary implants do not uniformly improve fixation of revision implants. This is due in large part to the devitalized sclerotic bone shell that typically forms during aseptic loosening. The smooth and relatively impermeable surface of the sclerotic bone barrier reduces shear attachment strength and acts as a barrier to the transport of cells and growth factors. Earlier we established that creating access across the barrier by a surgical technique ("cracking" the barrier) markedly improves fixation. In the last period we established that the clinical technique of reaming to remove the sclerotic barrier results in inferior fixation compared with cracking. For this funding period we have three aims, all with sclerotic bone barrier cracking;(i) to evaluate anabolic and anti-catabolic agents when access of the body's own marrow and blood vessels is established by sclerotic bone cracking, (ii) to apply multi-drug coatings with antimicrobial agents and growth factors and (iii) to augment bone graft with periosteum and synthetic bone graft extenders. We hypothesize (1) that grafted anabolic and anticatabolic agents will improve implant fixation, (2) that an antimicrobial coating does not impair fixation, and that fixation is improved when it is combined with an anabolic agent, and (3) that bone graft extenders (autologous periosteum and bioactive hydroxyapatite) will improve fixation compared with control. Fixation is determined mechanically (static and dynamic shear strength, stiffness and energy and damping modulus), histomorphometrically (bone ongrowth, % bone in peri-implant space, % fibrous tissue and % marrow at implant surface and in peri-implant space). Vascular growth is quantified with immunohistochemistry. While primary joint replacements provide the highest quality of life improvement per health care dollar spent, and have 95% survival at ten years, the number of revisions for failed primaries is rising due to the increasing pool of people with implanted devices and having longer life spans. The health care burden of revision surgery is high and rising: revisions comprise 20% of joint replacement surgeries, are complex and require specialized surgeon and hospital resources, have poorer function, and are more likely to become infected. Costs are expected to reach $50 billion in 2015, a rise of roughly 400% since 2005. PUBLIC HEALTH RELEVANCE: Our long term goal is to improve the clinical success of revised joint replacements by improving their fixation. We have three main approaches;(i) to improve the access of the body's own marrow and blood vessels, (ii) to apply multi-drug coatings with antimicrobial agents and growth factors, and (iii) to augment bone graft with periosteum and synthetic bone graft extenders. Revision implants comprise 20% of joint replacement surgeries and costs are expected to reach $50 billion in 2015, a rise of roughly 400% since 2005.